Factors V and VIII are procofactors which are essential components of the blood coagulation process. Deficiency in either of these proteins is associated with severe bleeding disorders, hemophilia and para-hemophilia. Deficiency states of these proteins can be caused by their proteolytic inactivation by Activated Protein C (APC), a natural anticoagulant enzyme. Therapeutic intervention in hemophilia-A through the use of replacement plasma factor VIII is a standard measure to control bleeding. It is logical to expect that selective inhibitors of APC might improve the efficacy of factor VIII replacement therapy by reducing the losses of Factor VIlla to APC cleavage. Inhibitors of APC which express reasonable affinity and high specificity have not been reported. Recent identification of the cleavage sites of Factors Va and VIlla by APC have led-to the development of synthetic peptide inhibitors with affinity for APC. These inhibitors did not inhibit thrombin and showed very low affinity for Factor Xa, raising the possibility that such inhibitors might selectively neutralize the anticoagulant effect of APc. Factor VIII replacement therapy is a 300 million dollar per year business in the United States alone. It is conceivable that by improving the prophylactic effect of this replacement therapy and/or alleviating the need for such therapy in border-line cases, as much as 100 million dollars per year could be saved in health care costs within the United States. This proposal has the following specific aims: l) further design and synthesis of specific APC inhibitors; 2) evaluation of the influence of these inhibitors on Thrombin and Factor Xa generation 3) evaluation of synthesized compounds in blood clotting assays.